Genome wide association studies are powerful for correlating human genotype to phenotype. These studies are designed to identify the polymorphisms in the genetic code that are most predictive of a phenotype. Rapid advances in genotyping technologies enable comprehensive coverage of the genome, including a majority of intergenic polymorphisms. Interestingly, when included in the association analysis, non-coding polymorphisms are often the most highly predictive of the phenotype. Furthermore, Single Nucleotide Polymorphisms (SNPs) are inherited together in Linkage Disequilibrium (LD) blocks. As a result, identifying the causative SNP in an LD block mapping to non-coding regions of the genome remains a contemporary computational and experimental challenge in the field of genomics. Although non-coding regions of the genome are not translated into protein, they are in a majority of cases transcribed in RiboNucleic Acid (RNA). Since RNA is a single stranded polymer, it will fold and the higher-order structures it adopts are integral to numerous RNA-mediated post-transcriptional regulatory functions in the cell. In detailed and focused studies of individual transcripts, our team has discovered that disruption of RNA structural features in non-coding regions of transcribed RNAs are causative in at least three human disease states - hyperferritinemia cataract syndrome, retinoblastoma and cartilage hair hypoplasia - and that altered RNA structure determines hepatitis C virus clearance efficiency. The vision of this proposal is to improve our computational ability to predict RiboSNitches (structural features in RNA that are disrupted by a SNP) by improving the accuracy of ensemble suboptimal structure sampling and pseudoknot prediction, and by using chemical structure probing data to characterize allele-specific RNA conformations, both in vitro and in healthy living cells in vivo. Ultimately, this work will substantially improve our ability to predict the causative disease-associated SNP in an LD block mapping to non-coding, intergenic regions of the human genome.